RNAi protects living animals against disease

For the first time, biologists have published a report showing how harnessing an ancient immune system in mammalian cells can protect living animals against disease.

The team used a technology known as RNA interference (RNAi) to halt hepatitis in mice. The result's are "pretty amazing, considering this represents our first attempt," says Judy Lieberman at Harvard Medical School in Boston. "We haven't optimised it at all."

If the technique works in humans, it represents a new treatment strategy for a huge variety of diseases and infections.

RNAi involves stimulating an attack on the messenger RNA that a gene sends to a cell's protein factory. This is achieved by designing tiny RNA molecules that match a sequence in the target gene.

Defense system

These small interfering RNAs (siRNAs) switch on a natural defense system, which cells use to destroy invading viruses and control gene activation. Once the system is activated, its molecular agents seek out and destroy their RNA target. This effectively shuts the gene off - and fights any disease the gene causes.

RNAi has been used in plants and worms for years, but was only recently discovered to work in mammalian cells. In 2001, a flurry of scientific articles demonstrated that RNAi could be used to attack viruses in human cells grown in the lab and even shut down genes in mice injected with siRNAs. But none of these proved the technology was efficient enough for effective therapy in living animals.

Now work by Lieberman and her colleagues shows it can be. Their target was the gene for the Fas protein which sits on the surface of cells and activates a cellular suicide program.

Many liver diseases result from the activation of Fas by viruses, immune system malfunction or chronic alcoholism. "The liver has a lot of Fas, so it is very sensitive to this death receptor," says Lieberman.

Crude delivery, good effect

Other researchers had shown that siRNAs simply injected into the tail veins of mice soon appear in the liver. When her team injected anti-Fas siRNAs into mice, nearly 90 percent of liver cells took up the molecules and Fas gene expression dropped by a factor of 10.

Then to mimic severe hepatitis, they injected mice with Fas antibodies to trigger the suicide program. The 40 control mice all died within three days. But 33 out of 40 mice that had been preinjected with siRNAs survived for 10 days. At that point the animals were killed and their livers examined. The organs appeared to be completely normal.

"I wouldn't have expected to see that good an effect in an organ, given the crude method of delivery," says Gregory Hannon, an RNAi researcher at Cold Spring Harbor Laboratory in New York. "It's quite a nice demonstration of how this might work as a therapeutic."

However, because humans are so much larger than mice, injecting siRNAs into the general blood stream is probably not a therapeutic option. But Lieberman and other researchers are already working on ways to target the siRNAs to specific organs.

Journal reference: Nature Medicine (DOI:10.1038/nm828)

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